| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nonalcoholic Steatohepatitis (NASH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| NASH is a chronic liver disease caused by the build-up of too much fat in the liver, along with inflammation and liver damage. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Randomized, Double-Blind, Placebo-Controlled Part:
• To evaluate the efficacy and safety of twice daily administration (BID) of Aramchol 300mg as compared to placebo in subjects with NASH and liver fibrosis.
Open Label Part:
• To evaluate the safety and PK of twice daily administration (BID) of Aramchol 300mg in subjects with NASH and liver fibrosis.
• To explore the kinetics of histological outcome measures and Non-Invasive Tests (NITs) associated with NASH and fibrosis for the treatment duration of 24, 48 and 72 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The inclusion criteria for the Open-Label Part are the same as those of the Randomized, Double-Blind, Placebo-Controlled Part with the
exception of fibrosis stage (the Open-Label Part allows enrollment of subjects with fibrosis stage 1), weight (the Open-Label Part allows
enrollment of subjects who are not overweight) and Type diabetes mellitus (the Open-Label Part allows enrollment of subjects who are not prediabetic or subjects who do not have type 2 diabetes mellitus).
1. Male or female age 18 to 75 years (inclusive at first Screening visit)
2. Histological confirmation of NASH on a diagnostic liver biopsy by central reading of the slides
• Open-Label Part: biopsy obtained within 9 months prior to randomization or during the screening period.
• Randomized, Double-Blind, Placebo-Controlled Part: biopsy obtained within 6 months prior to randomization or during the screening period.
3. Total NAS Score 4 or more with at least 1 in each component of the NAS Score (steatosis ≥1 AND inflammation ≥1 AND ballooning ≥1)
4. Fibrosis Stage must be 2 or 3
• Open-Label Part only: 30 subjects with fibrosis stage 1 may be included
5. Subjects who have had a biopsy more than 3 months before randomization should have stable weights between the time of the biopsy and screening. Stable weight is defined as no more than a 5 percent change
6. Body mass index (BMI)
• Open-Label Part: ≤ 40 kg/m2
• Randomized, Double-Blind, Placebo-Controlled Part: between 25kg/m2 and 40 kg/m2
7. The subject made at least one attempt of dietary and/or lifestyle change guided by professional counseling in the past and no new attempts to make dietary and/or lifestyle changes have been initiated within the 3 months prior to screening or is actively being sought now
8. Randomized, Double-Blind, Placebo-Controlled Part only: Type 2 diabetes mellitus or prediabetes: Type 2 diabetes diagnosis must be established and documented prior to screening. For prediabetes, unless pharmacologically treated, the diagnosis should be verified by screening results (by central lab) according to the American Diabetes Association criteria, which requires at least one of the following 3 criteria:
• Fasting Plasma Glucose 100 - 125 mg/dL (5.6 - 6.9 mmol/L)
• Post-load glucose (2hPG) following 75g oral glucose tolerance test
(OGTT) 140 - 199 mg/dL (7.8 -11.0 mmol/L)
• Glycosylated Hemoglobin (HbA1c) 5.7% - 6.4%
9. For subjects with type 2 diabetes, glycemia must be controlled (HbA1c ≤ 9%)
10. Negative blood pregnancy test at study entry for females of childbearing potential confirmed by central laboratory
11. Females of childbearing potential must practice a highly effective method of contraception at least 1 month prior to randomization, throughout the study period and for 1 month after treatment discontinuation
- A woman is considered of childbearing potential if fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
- Highly effective methods are defined as those that can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods, in accordance with the recommendations of the Clinical Trial Facilitation Group (CTFG) Working Group on Contraception include:
Hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner (vasectomised partner ia a highly effective birth control method provided that partner is the sole sexual partner of the trial participant and the vasectomised partner has received medical assessment of the surgical success), *sexual abstinence (abstinence is defined as refaining from heterosexual intercourse during the entire treatment period).
*In some countries sexual obstinence is not considered an acceptable method of contraception. Please refer to the approved ICFs to determine whether this method is considered acceptable.
12. Able to understand the nature of the study and to provide signature of the written informed consent.
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|
| E.4 | Principal exclusion criteria |
All exclusion criteria for the Open-Label Part are the same as those of the Randomized, Double-Blind, Placebo-Controlled Part.
1. Histologically documented liver cirrhosis (fibrosis stage 4)
2. Inability or unwillingness to undergo a liver biopsy
3. Abnormal synthetic liver function
• Albumin below the lower limit of the normal range
• International Normalized Ratio (INR) ≥ 1.3;
• Total bilirubin ≥ 1.3 mg/dL (22.2 μmol/L); subjects with a documented history of Gilbert's syndrome can be enrolled if the direct bilirubin is within normal reference range
4. ALT or AST >5× upper limit of normal (ULN); according to central laboratory
5. Platelet count < 150,000mm3
6. Alkaline phosphatase ≥2× ULN
7. Known or suspected hepatocellular carcinoma (HCC)
8. Model for End-Stage Liver Disease (MELD) score > 12 using OPTN formula
9. Prior history of/or planned liver transplantation
10. Prior history or presence of decompensated liver disease
11. Current or past evidence of portal hypertension (e.g., low platelet counts, esophageal varices, ascites, history of hepatic encephalopathy, splenomegaly)
12. Other (acute or chronic) coexisting liver disease based on medical history and/or centralized review of liver histology including:
• Subjects positive for hepatitis C antibodies unless sustained virologic response (SVR) is documented at least 3 years prior to screening and
confirmed at screening by central laboratory
• Subjects positive for Hepatitis B surface antigen (HBsAg)
• Primary biliary cholangitis (PBC)
• Primary sclerosing cholangitis (PSC)
• Genetic hemochromatosis
• Wilson's disease
• Alpha 1 antitrypsin deficiency
• Autoimmune hepatitis
• Alcoholic liver disease
• Drug-induced liver disease
13. Known alcohol and/or any other drug abuse or dependence in the last five years
• Daily alcohol intake will be an exclusion if >20 g/day for women and >30 g/day for men (on average per day), as per medical history
14. Human immunodeficiency virus HIV infection (either known or diagnosed during Screening blood tests)
15. Known familial (i.e., genetic) hypertriglyceridemia or familial (i.e., genetic) hypercholesterolemia
16. Diabetes Mellitus other than type 2 (type 1, endocrinopathy, genetic syndromes etc.)
17. Weight loss of more than 5% within 3 months prior to screening
18. History of bariatric surgery within 5 years of liver biopsy or planned surgery for weight reduction
19. Treatment with drugs that may cause NAFLD within 12 months prior to the biopsy (e.g. valproic acid, tamoxifen, methotrexate, amiodarone, chronic treatment with corticosteroids, high dose estrogen and tetracycline)
20. Treatment with Vitamin E unless started at least 12 months prior to biopsy, with stable dose in the 6 months prior to biopsy
• Subjects that stopped treatment less than 6 months prior to biopsy should be excluded
21. Treatment with GLP-1 receptor agonists or thiazolidinediones (TZDs) unless started at least 12 months prior to biopsy, with stable dose in the
6 months prior to biopsy
• Subjects that stopped treatment less than 6 months prior to biopsy should be excluded
22. Treatment with SGLT-2 inhibitors, metformin, sulfonylurea, insulin, and DPP-4 inhibitors unless the prescribed dose has been stable for 3 months prior to screening
23. Treatment with fibrates and statins unless the prescribed dose has been stable for 3 months prior to screening
24. Previous treatment with polyunsaturated fatty acid, ursodeoxycholic acid or fish oil unless stable for at least 6 months prior to screening or stopped at least 3 months prior to screening
25. Current or planned treatment with immunosuppressive drugs (e.g. adalimumab, azathioprine and methotrexate)
26. Evidence of any other unstable or untreated clinically significant hepatic, cardiovascular (including any clinically significant cardiovascular events within 3 months before screening), pulmonary, immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric disease
• History of cancer is allowed only following 5 years of remission
• Basal cell carcinoma or squamous cell carcinoma are allowed in case of a resected, noninvasive lesion
27. History or presence of any disease or condition known to interfere with the absorption, distribution, metabolism or excretion of drugs including bile salt metabolism (e.g. inflammatory bowel disease (IBD); major previous or planned intestinal operation (ileal or involving the right colon); chronic pancreatitis; celiac disease or previous vagotomy)
28. Chronic antibiotic treatment (e.g. rifaximin)
29. Uncontrolled hypertension:
• Hypertensive subjects must be controlled by stable dose of antihypertensive medication for at least 3 months prior to screening
30. Uncontrolled hypothyroidism defined as Thyroid Stimulating Hormone (TSH) >2× ULN. For subjects on thyroid replacement therapy, the dose of thyroxine should be stable for at least 6 months prior to screening
For full details, please refer to Protocol pages 54-56 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Randomized, Double-Blind, Placebo-Controlled Part:
1. Histology-Based: The Histology-Based primary endpoint will be derived from the week 72 biopsy of the initial 1000 subjects as compared to baseline biopsy and will use:
- Resolution of NASH defined as the Proportion (%) of subjects with resolution of NASH (defined by Ballooning of 0 and inflammation 0-1) and no worsening of liver fibrosis on NASH CRN fibrosis score (≥ 1 stage increase).
OR
- Improvement in Fibrosis defined as the Proportion (%) of subjects with improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation or steatosis)
2. Clinically-Based: The Clinically-Based primary endpoint is the time to first occurrence of any of the following adjudicated events:
- All-cause mortality
- Liver transplant
- Histological progression to cirrhosis
- MELD score >15 if baseline MELD score was <12
- Hospitalization due to hepatic decompensation event(s) including:
-Hepatic encephalopathy grade ≥2 (as assessed by West Haven
scale)
-Variceal bleeding
-New onset ascites requiring treatment
-Spontaneous bacterial peritonitis as assessed by either positive
cell culture or cell count
Open-Label Part:
The primary endpoints are the kinetics of histological outcome measures for treatment duration of 24, 48 and 72 weeks and potentially following a 2nd post-baseline biopsy at weeks 72 or 96 or 120 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Randomized, Double-Blind, Placebo-Controlled Part:
1) Histology based endpoint: after the initial 1000 subjects have passed the week 72 biopsy
2) Clinical based endpoint: at End of Study (EoS) which will occur at the time when a total of 380 subjects will experience at least 1 pre-specified clinical event or at 5 years from last subject's randomization, whichever comes first. |
|
| E.5.2 | Secondary end point(s) |
Randomized, Double-Blind, Placebo-Controlled Part:
1. At EoS, improvement in Fibrosis: 5-Year Proportion (%) of subjects with improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation or steatosis)
Open-Label Part:
The secondary endpoints are the kinetics of the following parameters and NITs for the treatment duration of 24, 48 and 72 weeks:
• ALT and AST
• Glycemic parameters
• Lipid parameters
• Fibroscan
• Biomarkers including but not limited to ProC3 and ELF Microbiome profile |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Randomized, Double-Blind, Placebo-Controlled Part:
1) Histology based endpoint: after the initial 1000 subjects have passed the week 72 biopsy
2) Clinical based endpoint: at End of Study (EoS) which will occur at the time when a total of 380 subjects will experience at least 1 pre-specified clinical event or at 5 years from last subject's randomization, whichever comes first. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Chile |
| Israel |
| Korea, Republic of |
| Mexico |
| Turkey |
| United States |
| Belgium |
| France |
| Germany |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of Study (EoS) is the time when a total of 380 subjects will experience at least 1 pre-clinical event or at 5 years from last subject's randomization, whichever comes first.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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